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INTRACELLULAR RECEPTORS (For Lipid Soluble Messengers) Function in the Nucleus As Transcription Factors to Alter the Rate of Transcription of Particular Genes

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INTRACELLULAR RECEPTORS (For Lipid Soluble Messengers) Function in the Nucleus As Transcription Factors to Alter the Rate of Transcription of Particular Genes MECHANISMS of chronic toxicity • Various chronic effects have uniform biochemical basis INTRACELLULAR TOXIN Biochemical In vivo RECEPTOR effects effects RECEPTORS HORMONE INTRACELLULAR RECEPTORS (for lipid soluble messengers) function in the nucleus as transcription factors to alter the rate of transcription of particular genes ¾ligand-activated transcription factors ¾crucial role in cell signaling ¾activation of different responsive elements (genes) SINGLE mechanism -> SEVERAL effects Types of signaling in multicellular => understanding to mechanisms organisms may predict effects 1) female reproduction disorders Estrogen receptor 2) male feminisation activation 3) tumor promotion 4) immunomodulations 5) developmental toxicity Modes of cell-cell signaling • Intracellular signal molecules are small, lipid- soluble molecules such as steroid hormones, 1. Direct cell-cell or cell-matrix retinoids, thyroid hormones, Vitamin D. (made 2. Secreted molecules. from cholesterol) • These molecules diffuse through plasma and A. Endocrine signaling. The signaling molecules are hormones secreted by endocrine cells and carried through the circulation system to act on nuclear membranes and interact directly with target cells at distant body sites. the transcription factors they control. B. Paracrine signaling. The signaling molecules released by one cell act on neighboring target cells. C. Autocrine signaling. Cells respond to signaling molecules that they themselves produce (response of the immune system to foreign antigens, and cancer cells). 1 The intracellular (nuclear) receptor superfamily Intracellular receptor Steroid hormones, thyroid hormones, retinoids and vitamin D HYDROPHOBIC: - Non-polar molecules - Gases - Steroids Sequence similarities and three functional regions – N-terminal region of variable length; in some receptors portions of this region act as activation domain – At the center, DNA binding domain, made of a repeat of C4- zinc finger motif – Near the C-terminal end, hormone binding domain, which may act as an activation or repression domain. • Steroid hormones are often required to dimerize with a partner to activate gene transcription • Receptors for vitamin D, retinoic acid and thyroid hormone Endocrine System bind to responsive elements as heterodimers • Second component of the heterdimer is RXR monomer (i.e, RXR-RAR; RXR-VDR) Regulation of transcription activity • Regulatory mechanisms differ for hetero-dimeric and homodimeric receptors • Heterodimeric receptors are exclusively nuclear; without ligand, they repress transcription by binding to their cognate sites in DNA • Homodimeric receptors are mostly cytoplasmic in the absence of ligands • Hormone binding leads to nuclear translocation of receptors • Absence of hormone causes the aggregation of receptor as a complex with inhibitor proteins, such as Hsp90 2 Endocrine System The endocrine system includes all the organs and tissues that produce hormones • Includes endocrine glands, which are specialized to secrete hormones • Also organs, like the liver, that secrete hormones in addition to other functions A hormone is a chemical that is secreted into extracellular fluid and carried by the blood - can therefore act at a distance from source - only targets with receptor can respond 13 Hypothalamo-pituitary axis - Regulation of hormone synthesis - Hypothalamus – Gonadotropin releasing hormone (GnRH) - Pituitary – folicle stimulating (FSH) and luteineising hormone (LH) Feedback Mechanisms Lipophilic Hormones • For hormone secretion regulated by the negative Lipophilic hormones include the steroid feedback loop: when hormones (derived from cholesterol) and gland X releases the thyroid hormones (tyrosine + iodine) hormone X, this stimulates target -As well as the retinoids, or vitamin A cells to release Cortisol (Hydrocortisone) Testosterone Thyroxine hormone Y. When CH2OH OH C O H C there is an excess of H C 3 II COOH HO 3 OH H3C HO O CH CH hormone Y, gland X H3C 2 II NH2 "senses" this and O inhibits its release of O hormone X. 18 3 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Blood 1. Hormone passes plasma through plasma Lipophilic Hormones membrane Lipophilic hormones These hormones circulate in the blood bound Plasma membrane to transport proteins Cytoplasm - Dissociate from carrier at target cells Nucleus 2. Inside target - Pass through the cell membrane and cell the hormone Receptor binds to a receptor protein 3. Hormone-receptor bind to an intracellular receptor, either in in the cytoplasm complex binds to or nucleus hormone response element on DNA, the cytoplasm or the nucleus 5. Change in protein regulating gene synthesis is transcription cellular response mRNA - Hormone-receptor complex binds to Protein DNA hormone response elements in DNA 4. Protein synthesis - Regulate gene expression Hormone response element 19 20 Steroid Hormones They include sex steroids (estrogen, progesterone, testosterone) corticosteroids (glucocorticoids and mineralcorticoids) Thyroid hormone, vitamin D3, and retinoic acid have different structure and function but share the same mechanism of action with the other steroids. • Steroid hormones and thyroid hormone diffuse easily into their target cells • Once inside, they bind and activate a specific intracellular receptor • The hormone-receptor complex travels to the nucleus and binds a DNA-associated receptor protein • This interaction prompts DNA transcription to produce mRNA • The mRNA is translated into proteins, which bring about a cellular effect Endocrine disruption • Interference of xenobiotics with normal function of hormonal system Possible consequences: Disruption of homeostasis, reproduction, development, and/or behavior. • Shift in sex ratio, defective sexual development • Low fecundity/fertility • Hypo-immunity, carcinogenesis • Malformations 4 biosynthesis and release of hormones Interaction with hormone system STEROIDOGENESIS e.g. modulation of CYP11A and/or CYP19 activities binding to plasmatic transport proteins e.g. down-regulation of receptor levels Synthesis binding to nuclear hormonal receptor (HR) activation of HR Transport Stimulation (dissociation of associated heat shock proteins, formation of homodimers) e.g. modulation of other nuclear receptors (PPAR/RXR, RXR/TR) Interaction with receptors binding of the activated receptor complex to specific DNA motifs - HREs Suppression Metabolization chromatin rearrangement and transcription of estrogen-inducible genes effects at the cellular, tissue, organ, organism, and/or population level Mechanisms of Endocrine disrupters in the steroid hormones signalling environment? disruption EDCs... • POPs and their metabolites - Illegitimate activation of hormonal receptor (HR) • steroid hormones and their derivatives from contraception pills - Binding to HR without activation • alkylphenols - Decrease of HR cellular levels • organometallics (butyltins) • pharmaceuticals - FSH/LH signalling disruption • pesticides - Changes in hormone metabolism OH OH OH ESTROGEN RECEPTOR - ER Estrogens: HO HO 17-β-estradiol estriol • play a key role in female hormone regulation and signalling • are responsible for metabolic, behavioural and morphologic changes occurring during stages of reproduction • are involved in the growth, development and homeostasis of a number of tissues • control the bone formation, regulation of homeostasis, cardiovascular system and behaviour • regulate production, transport and concentration of testicular liquid and anabolic activity of androgens in males 5 Estrogen receptor: ESTROGEN RECEPTORS - ER-α &ER-β: • a member of the nuclear hormone receptor superfamily • a ligand – inducible transcription factor • subtype: ER-α (in breast, ovary, brain, liver, bone and cardiovascular system, adrenals, testis and urogenital tract) ER-β (in kidneys, prostate and gastrointestinal tract) ER-γ (in fish) A/B D F C E Domains AF-1 AF-2 Transactivation Dimerization Nuclear localization Binding of Hsp90 Synthesis and metabolism of estrogens Mechanism of action of the estrogen hormones Cholesterol estradiol CYP11A + (20,22-lyáza) + TARGET CELL meziprodukt y Pregnenolon 17α-hydroxypregnenolon Dehydroepiandrosteron plasmatic transport CY P17 CYP17 protein NUCLEUS (17α-hydrox yláza) (17, 20-lyáza) estradiol Progesteron 17α-hydroxyprogesteron Androstendion Testosteron CYP 21 2-OH-estradiol ER CYP19 (21α-hydroxyláza) (aromatáza) CYP1A1 activation of ER CYP1B1 11-deoxykortikosteron 11-deoxykortisol Estron Estradiol 4-OH-estradiol 17β-HSD Estradiol β ? CYP11 sulfotrasnferáza (11β-hydroxyláza) Steroidní sulfatáza DNA 16-OH-estradiol protein Kortikosteron Kortisol Estron sulfát new synthesis mRNA biological proteins 18- hydr oxyláz a response Aldosteron Environmental estrogens (xenoestrogens, exoestrogens) Exoestrogens - examples are a diverse group of substances that do not necessarily share Natural products Industrial chemicals any structural resemblance to the prototypical estrogen (17β-estradiol) genistein Bisphenol A naringenin Nonionic surfactants but evoke effects resembling those of estrogen Pthalate esters coumestrol endosulfan • estrogenic substances (estrogen agonist) zearalenone • ANTI-estrogenic substances Environmental pollutant DEHP DDT kepone Pharmaceuticals PCBs/OH-PCBs Ethinyl estradiol PAHs and dioxins Diethylstilbestrol gestodene norgestrel 6 Exoestrogens - Relative Potencies to bind to ERα (REPs) Toxicity assessment - in vivo and in vitro methods Chemical group Substance REP Estradiol 1 Endogenous hormones Estriol 6,3.10-3
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